A 1β-methylcarbapenem derivative has an excellent antibacterial activity to pathogenic bacteria in a wide range including gram positive and gram negative microorganism; has particularly strong antibacterial activity even to cephem-resistant bacteria; and is excellent in stability in a living body. Therefore, the derivative has drawn attention as an antibacterial agent.
Such a 1β-methylcarbapenem derivative is synthesized by various methods. Azetidinonecarboxylic acid represented by the following formula (1):
is known as useful synthesis intermediate for the derivative, and many synthesis methods thereof are disclosed. In a synthesis method of the compound represented by the formula (1) (hereinafter, sometimes referred to as a “compound (1)”), the following methods are known as a method of obtaining crystal thereof:
A) a method of carrying out crystallization in water to obtain the crystal by acidifying an aqueous alkaline solution of the compound (1) with an aqueous hydrochloric acid solution (Patent Documents 1 and 2);
B) a method of acidifying an aqueous alkaline solution of the compound (1) with an aqueous hydrochloric acid solution; carrying out extraction with ethyl acetate; thereafter obtaining a crystalline solid substance by distillation of an ethyl acetate solution of the compound (1), which is obtained by drying with magnesium sulfate and filtration, under reduced pressure; and washing the solid substance with hexane to obtain the crystal (Patent Document 3);
C) a method of acidifying an aqueous alkaline solution of the compound (1) with an aqueous hydrochloric acid solution; carrying out extraction with ethyl acetate; concentrating the ethyl acetate solution of the compound (1), which is obtained by drying with magnesium sulfate and filtration, under reduced pressure; crystallizing from the residue by using an ethyl acetate and hexane solvent to obtain the crystal (Patent Document 4); and
D) a method extracting the compound (1) obtained by synthesis reaction with ethyl acetate, dissolving again the residue obtained by drying and concentration process in ethyl acetate, removing insoluble matter by filtration, concentrating the filtrate to obtain a crystalline solid, and re-crystallizing the solid from a mixed solvent of ethyl acetate and benzene to obtain the crystal (Patent Document 5).
However, the methods of obtaining the crystal have the following problems in term of a crystal recovery yield and a crystal purity of the compound (1):
low purity by the methods A) to C) and
low yield by the method D).
All of the above-mentioned methods have problems and thus are not satisfactory as a production method of the compound (1).
Further, as a result of studies by the inventors of the present invention, it was found that the above-mentioned methods A) to C) are inferior in the removal effect of a compound represented by the following formula (2) (hereinafter, sometimes referred to as “2S isomer”):
as a byproduct of the processes. In the synthesis of a precursor needed to produce the compound (1), investigations and researches relevant to a method of controlling byproduct production of a compound to be a precursor of the 2S isomer are positively carried out. The fact can be understood from Patent Documents 2 and 4. The methods A) to C) inferior in the 2S isomer removal effect are insufficient as a method for producing the compound (1) which is an intermediate of a pharmaceutical agent, since suppression of the content of the 2S isomer contained the crystal of the compound (1) are very critical issue.
Furthermore, the above-mentioned methods B) to D) are not satisfactory as a production method of the compound (1), since the methods involve a large number of complicated and non-economical operations from a viewpoint of industrial production scale. The operation is exemplified by drying of the ethyl acetate solution obtained with extraction of the compound (1) by using magnesium sulfate or the like and following filtration needed after the drying, recrystallization of the crystalline solid obtained by repeating concentration and dissolution, and the like.    Patent Document 1: JP 7-25848 A    Patent Document 2: JP 2000-44538 A    Patent Document 3: JP 5-105660 A    Patent Document 4: WO 2002/012230    Patent Document 5: JP 4-368365 A